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Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates.

Citation
Cunningham, C. N., et al. “Cells Deploy A Two-Pronged Strategy To Rectify Misfolded Proinsulin Aggregates.”. Molecular Cell, pp. 442-456.e4.
Center University of Michigan
Featured
Author Corey N Cunningham, Jeffrey M Williams, Jeffrey Knupp, Anoop Arunagiri, Peter Arvan, Billy Tsai
Keywords ER-phagy, Aggregates, endoplasmic reticulum, mutant proinsulin, protein quality control, reticulon
Abstract

Insulin gene coding sequence mutations are known to cause mutant INS-gene-induced diabetes of youth (MIDY), yet the cellular pathways needed to prevent misfolded proinsulin accumulation remain incompletely understood. Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby blocking insulin production. Two distinct quality-control mechanisms operate together to combat this insult: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogenic protein reticulon-3 (RTN3) disposes of aggregates via ER-coupled autophagy (ER-phagy). We show that enhanced RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, potentially alleviating MIDY. We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates.

Year of Publication
2019
Journal
Molecular cell
Volume
75
Issue
3
Number of Pages
442-456.e4
Date Published
12/2019
ISSN Number
1097-4164
DOI
10.1016/j.molcel.2019.05.011
Alternate Journal
Mol. Cell
PMID
31176671
PMCID
PMC6688957
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